The Beta-Arrestin-Biased Dopamine D(2) Receptor Ligand, UNC9994, Is a Partial Agonist at G-Protein-Mediated Potassium Channel Activation

BACKGROUND: Previous evidence suggests that UNC9994 is a beta-arrestin2-selective agonist at the dopamine D(2) receptor, lacking ability both to activate and antagonize G protein-dependent signaling. However, this has only been reported by one laboratory using a single assay. METHODS: We used G protein-coupled inward rectifier potassium channel activation in Xenopus oocytes to investigate UNC9994-induced modulation of G protein-dependent signaling at dopamine D(2) receptor and dopamine D(3) receptor. RESULTS: At dopamine D(2) receptor, UNC9994 induced G protein-coupled inward rectifier potassium channel currents that were 15% of the maximal response to dopamine, with an EC(50) of 185 nM. At dopamine D(3) receptor, the ligand elicited 89% of the maximal dopamine response with an EC(50) of 62 nM. Pertussis toxin abolished G protein-coupled inward rectifier potassium channel activation. Furthermore, UNC9994 antagonized dopamine-induced G protein-coupled inward rectifier potassium channel activation at dopamine D(2) receptor. CONCLUSIONS: UNC9994 modulates G protein-coupled inward rectifier potassium channel channel activation via pertussis toxin-sensitive G proteins at dopamine D(2) receptor and dopamine D(3) receptor. These findings may have implications for the interpretation of data obtained with this ligand.